Insulin release induced by the ingestion of glucose and other nutrients is due in part to both hormonal and neural factors (Creutzfeldt, et al., 1985, Diabetologia 28: 565–573). Several gastrointestinal regulatory peptides have been proposed as incretins, the substance(s) believed to mediate the enteroinsular axis and that may play a physiological role in maintaining glucose homeostasis (Unger, et al., 1969, Arch. Intern. Med, 123:261–266; Ebert, R., et al. 1987, Diab. Metab. Rev., 3:1–16; Dupré J., 1991, “The Endocrine Pancreas.” Raven Press, New York, p 253). Among these candidates, only glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (7–36) (GLP-1) appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (Dupré, et al. 1973, J. Clin. Endocrinol. Metab., 37:826–828; Nauck, et al., 1989, J. Clin. Endocrinol. Metab., 69:6540662; Kreymann, et al. 1987, Lancet, 2:1300–1304; Mojsov, et al., 1987, J. Clin. Invest., 79:616–619).
Following oral glucose administration, serum GIP levels increase several fold (see Cleator, et al., 1975, Am. J. Surg., 130:128–135; Nauck, et al. 1986, J. Clin. Endocrinol. Metab., 63:492–498; Nauck, et al., 1986, Diabetologia, 29:46–52; Salera, et al., 1983, Metabolism, 32:21–24; Kreymann, et al., 1987, Lancet, 2:1300–1304), and although the increment in plasma GLP-1 concentration in response to glucose is also significant, it is far smaller in magnitude (Kreymann, et al., 1987, Lancet, 2:1300–1304; Ørskov, et al., 1987, Scand. J. Clin. Invest., 47:165–174; Ørskov, et al., 1991, J. Clin. Invest., 87: 415–423; Shuster, et al., 1988, Mayo Clin. Proc., 63:794–800). In human volunteers, Nauck et al. (1993, J. Clin. Endocrinol. Metab., 76:912–917) showed that GIP and GLP-1 are major contributors in the incretin effect after oral glucose. Shuster et al. (1988) also suggested that GIP was the most important, but not the sole, mediator of the incretin effect in humans.
Some studies have demonstrated that GIP and GLP-1 are equally potent in their capacity to stimulate insulin release (Schmid, et al., 1990, Z. Gastroenterol., 28:280–284; Suzuki, et al., 1990, Diabetes, 39:1320–1325), whereas others have suggested that GLP-1 possesses greater insulinotropic properties (Siegel, et al. 1992, Eur. J. Clin. Invest. 22:154–157; Shima, et al. 1988, Regul. Pept., 22:245–252). Recently, using a putative specific antagonist to the GLP-1 receptor, exendin (9–39), Wang et al. have demonstrated that exendin reduced postprandial insulin release by 48% and thus concluded that GLP-1 might contribute substantially to postprandial stimulation of insulin secretion (Wang, et al. 1995, J. Clin. Invest., 95:417–421). More recent studies, however, have shown that exendin might also displace GIP binding from its receptor and thereby reduce GIP-stimulated cyclic adenosine monophosphate (cAMP) generation (Wheeler, et al. 1995, Endocrinology, 136:4629–4639: Gremlich, et al. 1995, Diabetes, 44:1202–1208). Therefore, the antagonist properties of exendin (9–39) might not be limited to GLP-1.
The availability of a GIP-specific receptor antagonist would be invaluable for determining the precise roles of these peptides in mediating postprandial insulin secretion.